The Genetics of Asthma
Abstract

Positional cloning led to the ability to identify ADAM33 as an asthma
susceptibility gene

Case-Control and family based association studies = almost confirmed link
between ADAM33 & asthma

ADAM 33 expressed in mesenchymal cells

Associated with bronchial hyperresponsiveness and accelerated lung function
o Suggests ADAM 33’s role in airway structure (ex. Remodeling)

Alternative splicing and tight epigenetic regulation = level of complexity in
association of ADAM33 and asthma phenotype

Role in COPD also points suggests role in airway structure (ex. Morphogenic
repair)
o ADAM33 effects are not contained to simply an asthma disease phenotype
Intro

Asthma is associated with a wide range of environmental factors

BHR (bronchial hyperresponsivness) and airway inflammation = 2 major
components of asthma

Not clear how inflammation relates to bronchial muscle hyperresponsiveness

Third phenotype of asthma becoming increasingly recognized
o Doesn’t respond to bronchiodialators or chorticosteroids

Characterized by epithelial damage and poor signaling between
epithelial and underlying mesenchymal cells

Signaling between the two is critical for branching
morphogenesis
The Discovery of Novel Asthma Genes

Asthma has strong genetic components but environmental factors need to be
present for these to manifest themselves

Linkage analysis of 260 families in UK and US led to region on chromosome
20p13
o ADAM 33 named a susceptibility gene
o Claim made that polymorphic variation in ADAM33 could have led to
50,000 cases of asthma in the UK
The Structure and Cellular Expression of ADAM 33

ADAM33 = 22 exons
o Domains of ADAM33


Signal sequence

Prodomain

Catalytic domain

Disintegrin domain

C-rich domain

EGF domain

Cytoplasmic domain (long 3’ untranslated region)
ADAM 33 mRNA is expressed in smooth muscle, fibroblasts and myofibroblasts
o Not in inflammatory or immune cells

Has a Ca binding site at the entrance of the active site of the catalytic domain

Demonstrated substrates of ADAM33
o Enzyme kinetics suggests they aren’t natural substrates

Stem cell factor

APP

Insulin B chain

TRANCE
Alternatively Spliced Variants of ADAM33

Analysis of fibroblasts = at least 6 variants of ADAM33
o None have catalytic domain
o 2% of all mRNA transcripts have metalloprotease domain
o selective nuclear transport is in favor of the full length molecule
o no clear difference between biopsies in the expression of each variant
between astmatic and WT
Regulation of ADAM 33 expression

CpG island in ADAM33 promoter seems critical in regulation of expression
o Island is hypermethlyated in epithelial cells but not fibroblasts
o Demethylation of CpG islands leads to expression of ADAM33 in H292
broncial epithelial cells

Reinforces the importance of epigenetic regulation in the
expression of ADAM33
Association of ADAM33 with asthma subphenotypes
